Human Philadelphia chromosome-positive (Ph+) leukemias induced by the BCR-ABL oncogene, including chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL), are among the most common hematologic malignancies. The BCR-ABL tyrosine kinase inhibitor STI571 (Gleevec) is highly effective in treating chronic phase CML patients, but is much less effective in treating CML blast crisis and Ph+ B-ALL patients. Moreover, the emerging clinical resistance to STI571 begs for development of new therapeutic strategies. Determination of the key signaling pathways utilized by BCR-ABL to induce B-ALL is crucial for understanding the pathophysiology of the disease and for developing effective therapies. We have established efficient and accurate mouse models of human Ph+ leukemias to test our overall hypothesis that BCR-ABL induces both lymphoid and myeloid leukemias, but different signaling pathways are utilized in these two cell lineages. In support of this hypothesis, we identified three Src family kinases (Lyn, Hck, and Fgr) as key signaling molecules in the development of BCR-ABL-induced B-ALL but not CML (Nature Genetics 36,453-461, 2004). Therefore, we hypothesize that Src kinase signaling pathways in BCR-ABL-expressing lymphoid cells are different from those in myeloid cells. We have also found that inhibition of BCR-ABL kinase by STI571 does not reduce BCR-ABL-stimulated Src activation, whereas use of a Src kinase inhibitor reduces proliferation and induces apoptosis of BCR-ABL-expressing cells that are resistant to ST1571. These results suggest that the activation of Src kinases is independent of BCR-ABL kinase activity. Therefore, we further hypothesize that simultaneous inhibition of functions of both BCR-ABL kinase (by STI571) and Src kinases (by a Src kinase inhibitor) is needed for therapy of Ph+ B-ALL. To test these hypotheses, we will take biochemical and genetic approaches to study the molecular mechanism by which Src kinases are activated by BCR-ABL and are involved in BCR-ABL signaling in B-lymphoid cells and B-ALL development. We will also further evaluate the use of Src kinases as therapeutic targets for B-ALL using our mouse model.